The effective therapy of multidrug resistant (MDR) tumors remains an important unsolved problem in cancer therapy. Certain proteins over-expressed in MDR cells, such as P-glycoprotein (Pgp) or survivin, are involved in the resistance of these cells towards traditional chemotherapy. Specific down-regulation of such proteins in cancer cells can be achieved by applying the corresponding siRNA. The combination of this approach and traditional chemotherapy could provide a promising strategy against MDR tumors. The clinical use of siRNA is limited by problems with its stabilization and delivery. We have recently suggested a poly(ethylene glycol)-phosphatidyl ethanolamine (PEG-PE)-modified G(4)-PAMAM nanocarrier for siRNA. We have also developed a unique dendrimer-based mixed micellar system from this new G(4)- PAMAM-PEG-PE and PEG-PE constructs. Such micelles can complex siRNA via the dendrimer part and entrap poorly soluble anti-cancer drugs within their lipid core. Such a system has high micellization efficiency with low CMC and higher drug loading; stabilizes and protects siRNA against enzymatic degradation; provides enhanced cell binding, penetration, and endosomal escape because of its positive charge; and shows less cytotoxicity due to PEGylation. It will allow a co-delivery of siRNA and drug in one nanopreparation, including the targeted one if the dendrimer-based micelles are surface-modified with the targeting ligand. Our general hypothesis is that PEG-lipid-modified dendrimer-based polymeric mixed micelles will complex siRNA via the dendrimer part and load poorly soluble anticancer drugs into the core resulting in siRNA/drug-co-loaded nanopreparations, which can be additionally targeted to tumor by surface- attached anti-cancer antibodies (mAb 2C5 developed by us earlier), and will serve as an effective mean against MDR tumors. The following specific aims will be pursued: (1) To prepare, characterize, and evaluate PAMAM-PEG-PE/siRNA (P-gp and survivin siRNAs) complexes and their mixed micellar nanopreparations with PEG-PE and anti-cancer drugs (doxorubicin or paclitaxel) modified or non-modified with mAb 2C5; (2) To study the interaction of non-targeted or Ab-targeted siRNA/drug-co-loaded dendrimer-based nanopreparations from the Aim 1 with various MDR cancer cells in vitro using non-MDR cells as controls: (a) To follow cell association and intracellular accumulation of siRNA and drugs; (b) Investigate the efficiency of the nanopreparations in down-regulation of target genes in MDR cells; (c) Evaluate their cytotoxicity and MDR reversal in MDR cells using scrambled siRNA as control; (3) To demonstrate the possibility of efficient siRNA/drug co-delivery to MDR tumors and enhanced tumor therapy using the developed systems in two different in vivo models and treatment agents selected after the Aim 2: (a) To investigate tumor accumulation of chosen non-targeted and targeted siRNA/drug-co-loaded nanopreparations in tumor-bearing mice; (b) To evaluate their activity in tumor growth inhibition using scrambled siRNA as a control.